SIRT7,a sirtuin family member implicated in aging and disease,is a regulator of metabolism and stress responses.It remains elusive how human somatic stem cell populations might be impacted by SIRT7.Here,we found that ...SIRT7,a sirtuin family member implicated in aging and disease,is a regulator of metabolism and stress responses.It remains elusive how human somatic stem cell populations might be impacted by SIRT7.Here,we found that SIRT7 expression declines during human mesenchymal stem cell(hMSC)aging and that SIRT7 deficiency accelerates senescence.Mechanistically,SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins,thus maintaining the repressive state of heterochromatin at nuclear periphery.Accordingly,deficiency of SIRT7 results in loss of heterochromatin,derepression of the LINE1 retrotransposon(LINE1),and activation of innate immune signaling via the cGAS-STING pathway.These agingassociated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor.Together,these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.展开更多
Silent information regulator 2 （Sir2） proteins, or sirtuins, are nicotine adenine dinucleotide （NAD）-dependent deacetylases that connect metabolism with longevity in lower organisms. In mammals, there are seven Si...Silent information regulator 2 （Sir2） proteins, or sirtuins, are nicotine adenine dinucleotide （NAD）-dependent deacetylases that connect metabolism with longevity in lower organisms. In mammals, there are seven Sir2 homologs, namely, silent information regulators （SIRT1-7）. SIRT4 and SIRT7 genes play a crucial role in regulating lipid metabolism, cellular growth and metabolism. This suggests that they are potential candidate genes for affecting body size and meat quality traits in animals. Hence, this study aimed to detect genetic variations of both SIRT4 and SIRT7 bovine genes in Qinchuan cattle, and to evaluate the effect of these variations on economically important body size and meat quality traits. Expression analysis using quantitative real-time PCR （qPCR） indicated that SIRT4 and SIRT7 were broadly expressed in all thirteen studied tissues. The expression of SIRT4 was higher in liver, muscle, and in subcutaneous fat tissue. In the case of SIRT7, the expression was higher in lung, abomasum, and subcutaneous fat. Using DNAsequencing, a total of three single nucleotide polymorphisms （SNPs） were identified within SIRT4 and SIRT7 genes in 468 Qinchuan cattle. These included one novel SNP within 3＇ untranslated regions （UTR） of SIRT4 （SNP1： g. 13915A〉G） and two novel synonymous substitutions in SIRT7 （SNP2： g.3587C〉T and SNP3： g.3793T〉C）. Statistical analyses indicated that all three SNPs could significantly influence some body size and meat quality traits in Qinchuan cattle. These novel findings will provide a background for application of bovine SIRT4 and SIRT7 genes in the selection program of Chinese cattle.展开更多
目的:受肝纤维化影响的人群广泛,而治疗方法缺乏。沉默信息调节因子2相关酶类7(silencing information regulator 2 related enzyme,SIRT7)是组蛋白去乙酰化酶sirtuin家族的成员,参与细胞衰老、代谢和炎症反应等多种生理学过程。据报道,...目的:受肝纤维化影响的人群广泛,而治疗方法缺乏。沉默信息调节因子2相关酶类7(silencing information regulator 2 related enzyme,SIRT7)是组蛋白去乙酰化酶sirtuin家族的成员,参与细胞衰老、代谢和炎症反应等多种生理学过程。据报道,SIRT7在许多肝脏疾病如肝癌和脂肪性肝炎中发挥重要作用,本研究旨在探究SIRT7在肝纤维化中的功能。方法:通过四氯化碳(CCl_(4))隔天腹腔注射,在野生型小鼠和肝细胞SIRT7特异性敲除小鼠中建立肝纤维化模型并进行损伤与纤维化表型测定。采用原代细胞分离与纯化技术进行体外共培养实验,结合阵列图进一步分析确定SIRT7缺失影响肝星状细胞(hepatic stellate cells,HSC)激活的分子媒介。结果:SIRT7缺失加剧了CCl_(4)诱导的肝损伤和纤维化表型。进一步研究表明,SIRT7缺失介导肝细胞PAI-1分泌差异激活HSC从而促进肝纤维化。结论:SIRT7介导的信号在肝损伤和纤维化中发挥重要作用,靶向SIRT7可能是治疗肝纤维化的有效途径。展开更多
A large body of evidence shows that a single bout of strenuous exercise induces oxidative stress in circu- lating human lymphocytes leading to lipid peroxide- tion, DNA damage, mitochondrial perturbations, and protein...A large body of evidence shows that a single bout of strenuous exercise induces oxidative stress in circu- lating human lymphocytes leading to lipid peroxide- tion, DNA damage, mitochondrial perturbations, and protein oxidation. In a training experiment, Wistar rats were divided into control group (CG) and exer- cise group (EG). After a running level exercise until exhaustion, we observed an increase in the mRNA content and protein expression of SIRT1 and SIRT7 in the EG compared to the CG. Moreover, such train- ing exercise did not change mRNA transcripts and protein expression of FOXO3A and GADD45. We also observed an increase of pro-apoptotic protein bax and a decrease of the anti-apoptotic protein bcl-2 in the EG. Accordingly, we observed a caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage only in EG rats. Statistical analysis of the data showed a significant correlation between SIRT1 and SIRT7 expression and apoptotic proteins such as bax, bcl-2 in both tissues. We conclude that, in both muscle, such exercise activates both a damaging apoptotic mecha- nism with bax increase and bcl-2 decrease and a counterbalancing protective mechanism with SIRT1 and SIRT7 increase.展开更多
Melanoma is the most lethal type of skin cancer,originating from the malignant transformation of melanocyte.While the development of targeted therapy and immunotherapy has gained revolutionary advances in potentiating...Melanoma is the most lethal type of skin cancer,originating from the malignant transformation of melanocyte.While the development of targeted therapy and immunotherapy has gained revolutionary advances in potentiating the therapeutic effect,the prognosis of patients with melanoma is still suboptimal.During tumor progression,melanoma frequently encounters stress from both endogenous and exogenous sources in tumor microenvironment.SIRT7 is a nuclear-localized deacetylase of which the activity is highly dependent on intracellular nicotinamide adenine dinucleotide(NAD+),with versatile biological functions in maintaining cell homeostasis.Nevertheless,whether SIRT7 regulates tumor cell biology and tumor immunology in melanoma under stressful tumor microenvironment remains elusive.Herein,we reported that SIRT7 orchestrates melanoma progression by simultaneously promoting tumor cell survival and immune evasion via the activation of unfolded protein response.We first identified that SIRT7 expression was the most significantly increased one in sirtuins family upon stress.Then,we proved that the deficiency of SIRT7 potentiated tumor cell death under stress in vitro and suppressed melanoma growth in vivo.Mechanistically,SIRT7 selectively activated the IRE1α-XBP1 axis to potentiate the pro-survival ERK signal pathway and the secretion of tumorpromoting cytokines.SIRT7 directly de-acetylated SMAD4 to antagonize the TGF-β-SMAD4 signal,which relieved the transcriptional repression on IRE1αand induced the activation of the IRE1α-XBP1 axis.Moreover,SIRT7 up-regulation eradicated anti-tumor immunity by promoting PD-L1 expression via the IRE1α-XBP1 axis.Additionally,the synergized therapeutic effect of SIRT7 suppression and anti-PD-1 immune checkpoint blockade was also investigated.Taken together,SIRT7 can be employed as a promising target to restrain tumor growth and increase the effect of melanoma immunotherapy.展开更多
文摘SIRT7,a sirtuin family member implicated in aging and disease,is a regulator of metabolism and stress responses.It remains elusive how human somatic stem cell populations might be impacted by SIRT7.Here,we found that SIRT7 expression declines during human mesenchymal stem cell(hMSC)aging and that SIRT7 deficiency accelerates senescence.Mechanistically,SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins,thus maintaining the repressive state of heterochromatin at nuclear periphery.Accordingly,deficiency of SIRT7 results in loss of heterochromatin,derepression of the LINE1 retrotransposon(LINE1),and activation of innate immune signaling via the cGAS-STING pathway.These agingassociated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor.Together,these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.
基金supported by the National 863 Program of China (2013 AA102505)the National Natural Science Foundation of China (31272411 and 31402044)+2 种基金the National Beef and Yak Industrial Technology System,China (CARS-38)the China Postdoctoral Science Foundation (2016M590976)the Key Technologies R&D Program of Henan Province,China (122102110062)
文摘Silent information regulator 2 （Sir2） proteins, or sirtuins, are nicotine adenine dinucleotide （NAD）-dependent deacetylases that connect metabolism with longevity in lower organisms. In mammals, there are seven Sir2 homologs, namely, silent information regulators （SIRT1-7）. SIRT4 and SIRT7 genes play a crucial role in regulating lipid metabolism, cellular growth and metabolism. This suggests that they are potential candidate genes for affecting body size and meat quality traits in animals. Hence, this study aimed to detect genetic variations of both SIRT4 and SIRT7 bovine genes in Qinchuan cattle, and to evaluate the effect of these variations on economically important body size and meat quality traits. Expression analysis using quantitative real-time PCR （qPCR） indicated that SIRT4 and SIRT7 were broadly expressed in all thirteen studied tissues. The expression of SIRT4 was higher in liver, muscle, and in subcutaneous fat tissue. In the case of SIRT7, the expression was higher in lung, abomasum, and subcutaneous fat. Using DNAsequencing, a total of three single nucleotide polymorphisms （SNPs） were identified within SIRT4 and SIRT7 genes in 468 Qinchuan cattle. These included one novel SNP within 3＇ untranslated regions （UTR） of SIRT4 （SNP1： g. 13915A〉G） and two novel synonymous substitutions in SIRT7 （SNP2： g.3587C〉T and SNP3： g.3793T〉C）. Statistical analyses indicated that all three SNPs could significantly influence some body size and meat quality traits in Qinchuan cattle. These novel findings will provide a background for application of bovine SIRT4 and SIRT7 genes in the selection program of Chinese cattle.
文摘目的:受肝纤维化影响的人群广泛,而治疗方法缺乏。沉默信息调节因子2相关酶类7(silencing information regulator 2 related enzyme,SIRT7)是组蛋白去乙酰化酶sirtuin家族的成员,参与细胞衰老、代谢和炎症反应等多种生理学过程。据报道,SIRT7在许多肝脏疾病如肝癌和脂肪性肝炎中发挥重要作用,本研究旨在探究SIRT7在肝纤维化中的功能。方法:通过四氯化碳(CCl_(4))隔天腹腔注射,在野生型小鼠和肝细胞SIRT7特异性敲除小鼠中建立肝纤维化模型并进行损伤与纤维化表型测定。采用原代细胞分离与纯化技术进行体外共培养实验,结合阵列图进一步分析确定SIRT7缺失影响肝星状细胞(hepatic stellate cells,HSC)激活的分子媒介。结果:SIRT7缺失加剧了CCl_(4)诱导的肝损伤和纤维化表型。进一步研究表明,SIRT7缺失介导肝细胞PAI-1分泌差异激活HSC从而促进肝纤维化。结论:SIRT7介导的信号在肝损伤和纤维化中发挥重要作用,靶向SIRT7可能是治疗肝纤维化的有效途径。
文摘A large body of evidence shows that a single bout of strenuous exercise induces oxidative stress in circu- lating human lymphocytes leading to lipid peroxide- tion, DNA damage, mitochondrial perturbations, and protein oxidation. In a training experiment, Wistar rats were divided into control group (CG) and exer- cise group (EG). After a running level exercise until exhaustion, we observed an increase in the mRNA content and protein expression of SIRT1 and SIRT7 in the EG compared to the CG. Moreover, such train- ing exercise did not change mRNA transcripts and protein expression of FOXO3A and GADD45. We also observed an increase of pro-apoptotic protein bax and a decrease of the anti-apoptotic protein bcl-2 in the EG. Accordingly, we observed a caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage only in EG rats. Statistical analysis of the data showed a significant correlation between SIRT1 and SIRT7 expression and apoptotic proteins such as bax, bcl-2 in both tissues. We conclude that, in both muscle, such exercise activates both a damaging apoptotic mecha- nism with bax increase and bcl-2 decrease and a counterbalancing protective mechanism with SIRT1 and SIRT7 increase.
基金The research leading to these results has received funding from National Natural Science Foundation of China(No.81902791,82173395)Support Program of Young Talents in Shaanxi Province(No.20200303,No.2022SF-178)Young Eagle Project of Fourth Military Medical University(No.2019cyjhgwn).
文摘Melanoma is the most lethal type of skin cancer,originating from the malignant transformation of melanocyte.While the development of targeted therapy and immunotherapy has gained revolutionary advances in potentiating the therapeutic effect,the prognosis of patients with melanoma is still suboptimal.During tumor progression,melanoma frequently encounters stress from both endogenous and exogenous sources in tumor microenvironment.SIRT7 is a nuclear-localized deacetylase of which the activity is highly dependent on intracellular nicotinamide adenine dinucleotide(NAD+),with versatile biological functions in maintaining cell homeostasis.Nevertheless,whether SIRT7 regulates tumor cell biology and tumor immunology in melanoma under stressful tumor microenvironment remains elusive.Herein,we reported that SIRT7 orchestrates melanoma progression by simultaneously promoting tumor cell survival and immune evasion via the activation of unfolded protein response.We first identified that SIRT7 expression was the most significantly increased one in sirtuins family upon stress.Then,we proved that the deficiency of SIRT7 potentiated tumor cell death under stress in vitro and suppressed melanoma growth in vivo.Mechanistically,SIRT7 selectively activated the IRE1α-XBP1 axis to potentiate the pro-survival ERK signal pathway and the secretion of tumorpromoting cytokines.SIRT7 directly de-acetylated SMAD4 to antagonize the TGF-β-SMAD4 signal,which relieved the transcriptional repression on IRE1αand induced the activation of the IRE1α-XBP1 axis.Moreover,SIRT7 up-regulation eradicated anti-tumor immunity by promoting PD-L1 expression via the IRE1α-XBP1 axis.Additionally,the synergized therapeutic effect of SIRT7 suppression and anti-PD-1 immune checkpoint blockade was also investigated.Taken together,SIRT7 can be employed as a promising target to restrain tumor growth and increase the effect of melanoma immunotherapy.
